Two types of frequency-dependent block of sodium channels have been observed when local anesthetics are applied internally to voltage clamped giant axons of squids. The one requires the intactness of sodium inactivation mechanism (h-gate) and the other does not require an intactness of h-gate. The frequency dependency of the latter remains unchanged or only slightly modified after h-gate has been destroyed by pronase treatment. Local anesthetics with smaller molecules usually exhibit the former type of block. Procaine, QX-314, QX-222, and 9-aminoacridine are some of these type of local anesthetics. Local anesthetics with bulky molecule having two phenyl ring or with equivalent lipophilic group such as long chain alkyl group exhibit the latter type of frequency-dependent block. These compounds include QX-572, lobeline, spin-labeled tetracaine derivatives and long chain derivatives of tetraamonium compounds. From these results, we propose that there is a hydrophobic component in the receptor for Na channel blocker. This view is also supported by our studies on interaction of alkylguanidine derivatives with Na channel. Lengthening the chain length enhances the potency in blocking Na channel. The longer chain derivative, octylguanidine, exhibits frequency-dependent block of Na channels. Antiarrhythmic drugs such as quinidine, procainamide, lidocaine, propranolol and phenytoin exhibit this frequency-dependent block of Na channels in squid axons. It remains to be seen whether all of these compounds exhibit frequency dependent inhibition of maximum rate of rise of action potential in cardiac tissues or not.